Method of inhibiting seborrhea and acne

ABSTRACT

A method of inhibiting acne or seborrhea comprising administering to a human in need of treatment an effective amount of a compound having the formula ##STR1## wherein R 1  and R 3  are independently hydrogen, --CH 3 , ##STR2## wherein Ar is optionally substituted phenyl; R 2  is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.

BACKGROUND OF THE INVENTION

Acne and seborrhea are two general classes of skin diseases which aremarked by an abnormal function (usually hyperactivity) of the sebaceousglands in the skin. The subject of this invention is the use ofcompounds to inhibit acne and seborrhea.

Acne vulgaris is a disease of the pilosebaceous unit in the skin and ischronic and inflammatory in nature. It is characterized by comedos(blackheads), papules, pustules, cysts, and nodules. The areas of thebody most commonly affected by the disease are those which have the mostsebaceous glands, i.e., the face, neck, back, and chest. Acne is verycommon disease in both men and women and usually appears at thebeginning of puberty. Although, the disease is usually mild and resolvesitself by the time most people reach their midtwenties, it can in manyinstances be disfiguring and a source of great physiological distress.In some extreme cases, acne can be the source of severe infection andeven life-threatening.

The etiology and pathogenesis of the disease begins with cohesivehyperkeratosis in which cornified cells adhere and block the follicularcanal between the sebaceous gland and the surface of the skin. Thesebaceous gland under hormonal control (testosterone anddihydrotestostrone) are stimulated to enlarge and produce increasingamounts sebaceous secretions (principally in the form oftriacylglycerols). These sebaceous secretions are trapped in theblocked, follicular canal and build up to form a closed comedo. At thisstage, common, indigenous skin bacteria (principally, PropionibacterumAcnes) begin to metabolize the triacylglycerols to free fatty acids.These liberated fatty acids are inflammatory and results in theformation of a papule. This papule is often raised and is typical of aninflammatory lesion, i.e., red, edematous, and painful. The papule maycontinue to expand and rupture the follicle wall, thus forming a pustuleor cyst. The pustule stage is very painful and unsightly and is often asite for secondary infection by opportunistic bacteria such asStaphofius. The pustules and cysts often lead to the scarring anddisfigurement seen in severe cases of acne.

There are several drugs available for the treatment of acne. For mildcases, benzoyi peroxide is used and is often moderately effective.Benzoyl peroxide is thought to work by inhibiting cohesivehyperkeratosis and by suppressing P. Aches. although benzoyl peroxide iseffective in mild cases of acne, it suffers from several drawbacks:first, it must be applied topically and does not always penetrate to thepilosebaceous unit where the acne lesion initiates, second, it can causeskin irritation which can exacerbate the disease. Another moderatelyeffective drug is vitamin A (retenoic acid, Retin-A) which is usedtopically. Vitamin A inhibits cohesive hyperkeratosis; however, being atopical preparation it suffers from some of the same drawbacks asbenzoyl peroxide and in addition it can cause a deterioration of theprotective stratum corneum if used extensively. Yet another group ofcommonly used drugs for the treatment of acne are antibiotics. These canbe used either topically or systemically. The most commonly usedantibiotics are tetracyclines and erythromycin and to a lesser extentminocycline, ampicillin, clindamycin, trimethoprim, andsulfamethoxazole. These antibiotics inhibit P. Aches and other secondarybacterial infections. There are two major drawbacks to the prolonged useof antibiotics for acne; first, the continued long exposure toantibiotics often lead to formation of resistant bacterial strains bothin the skin and systemically, and second continued use of antibioticsmay lead to sensitization of the patient to the antibiotic. A newer drugused for acne is Isotretinoin (Accutane, 13-cis-retenoic acid). Thisdrug works like vitamin A; however, it can be used systemically. Theside-effects of isotretinoin are often: cheiliris, a rise in serumtriglycerides, elevated sedimentation rates, and most importantly,isotretinoin is a teratogen in humans and therefore cannot be used ifthere is a question of pregnancy during treatment. All of the abovedrugs have some positive effect in the treatment of acne, but each hasits limiting side-effects.

Hormonal therapy is also effective for the treatment of acne in women.In many cases, the administration of estrogens has a positive effect intreating acne. Estrogens counteract the effect endogenous androgens andtherefore, decrease sebaceous excretion. However, since the use ofunopposed estrogen administration in women with a uterus poses thepotential for the development of endometrial cancer, a cyclic therapy ofestrogen and a progestin are used for the treatment of acne. Typically,women are prescribed the normal birth control protocols for acnetreatment. Although, these protocols are often effective for acne, inmany cases these regiments contain progestins which have significantandrogenic activity. This androgenic activity exacerbates the disease.Additionally, it is well known that progestinal agents are the cause ofmany negative, psychological side-effects. Clearly, a better hormonalagent would be beneficial.

Seborrhea or seborrheic dermatitis is another group of skin diseasesthought to be associated with abnormal function of the sebaceous glands.It occurs in areas where there are large numbers of sebaceous glands andis characterized by flaking of the skin and red, mildly inflammatorypatches. Seborrhea is most common in the hair (a form of dandruff),scalp margins, eyebrows, naso-labial folds, external ear canals, postierauricular fold, and presternal area. Generally, mild seborrhea iscontrolled by topical medication such as glucocorticoids and LDH inNivea oil. However, more severe cases are more difficult to control.

SUMMARY OF THE INVENTION

This invention provides methods for inhibiting acne or seborrheacomprising administering to a human in need of treatment an effectiveamount of a compound of formula I ##STR3## wherein R¹ and R³ areindependently hydrogen, --CH₃, ##STR4## wherein Ar is optionallysubstituted phenyl;

R² is selected from the group consisting of pyrrolidino,hexamethyleneimino, and piperidino; and pharmaceutically acceptablesalts and solyates thereof.

DETAILED DESCRIPTION OF THE INVENTION

The current invention concerns the discovery that a select group of2-phenyl-3-aroylbenzothiophenes (benzothiophenes), those of formula I,are useful for inhibiting acne or seborrhea. The methods of treatmentprovided by this invention are practiced by administering to a human inneed of a dose of a compound of formula I or a pharmaceuticallyacceptable salt or solrate thereof, that is effective to inhibit acne orseborrhea. The term inhibit is defined to include its generally acceptedmeaning which includes prophylactically treating a human subject toincurring the conditions described, and holding in check and/or treatingexisting conditions. As such, the present method includes both medicaltherapeutic and/or prophylactic treatment, as appropriate.

Raloxifene, a compound of this invention wherein it is the hydrochloridesalt of a compound of formula 1, R¹ and R³ are hydrogen and R² is1-piperidinyl, is a nuclear regulatory molecule. Raloxifene has beenshown to bind to the estrogen receptor and was originally thought to bea molecule whose function and pharmacology was that of an anti-estrogenin that it blocked the ability of estrogen to activate uterine tissueand estrogen dependent breast cancers. Indeed, raloxifene does block theaction of estrogen in some cells; however in other cell types,Raloxifene activates the same genes as estrogen does and displays thesame pharmacology, e.g., osteoporosis, hyperlipidemia. As a result,raloxifene has been referred to as an anti-estrogen with mixedagonist-antagonist properties. The unique profile which raloxifenedisplays and differs from that of estrogen is now thought to be due tothe unique activation and/or suppression of various gene functions bythe raloxifene-estrogen receptor complex as opposed to the activationand/or suppression of genes by the estrogen-estrogen receptor complex.Therefore, although Raloxifene and estrogen utilize and compete for thesame receptor, the pharmacological outcome from gene regulation of thetwo is not easily predicted and is unique to each.

Generally, the compound may be formulated with common excipients,diluents or carriers, and compressed into tablets, or formulated aselixirs or solutions for convenient oral administration, administered bythe intramuscular or intravenous routes, or administered topically. Thecompounds can be administered transdermally, and may be formulated assustained release dosage forms and the like.

The compounds used in the methods of the current invention can be madeaccording to established procedures, such as those detailed in U.S. Pat.Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporatedby reference herein. In general, the process starts with abenzo[b]thiophene having a 6-hydroxyl group and a 2-(4-hydroxyphenyl)group. The starting compound is protected, acylated, and deprotected toform the formula I compounds. Examples of the preparation of suchcompounds are provided in the U.S. patents discussed above. Substitutedphenyl includes phenyl substituted once or twice with C₁ -C₆ alkyl, C₁-C₄ alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro orfluoro)methyl.

The compounds used in the methods of this invention formpharmaceutically acceptable acid and base addition salts with a widevariety of organic and inorganic acids and bases and include thephysiologically acceptable salts which are often used in pharmaceuticalchemistry. Such salts are also part of this invention. Typical inorganicacids used to form such salts include hydrochloric, hydrobromic,hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like.Salts derived from organic acids, such as aliphatic mono anddicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoicand hydroxyalkandioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, may also be used. Such pharmaceutically acceptable saltsthus include acetate, phenylacetate, trifluoroacetate, acrylate,ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, o-acetoxybenzoate,naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate,β-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate,caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate,heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate,malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate,oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate,propionate, phenylpropionate, salicylate, sebacate, succinate, subcrate,sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate,benzene-sulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate,ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate,xylenesulfonate, tartarate, and the like. A preferred salt is thehydrochloride salt.

The pharmaceutically acceptable acid addition salts are typically formedby reacting a compound of formula I with an equimolar or excess amountof acid. The reactants are generally combined in a mutual solvent suchas diethyl ether or benzene. The salt normally precipitates out ofsolution within about one hour to 10 days and can be isolated byfiltration or the solvent can be stripped off by conventional means.

Bases commonly used for formation of salts include ammonium hydroxideand alkali and alkaline earth metal hydroxides, carbonates, as well asaliphatic and primary, secondary and tertiary amines, aliphaticdiamines. Bases especially useful in the preparation of addition saltsinclude ammonium hydroxide, potassium carbonate, methylamine,diethylamine, ethylene diamine and cyclohexylamine.

The pharmaceutically acceptable salts generally have enhanced solubilitycharacteristics compared to the compound from which they are derived,and thus are often more amenable to formulation as liquids or emulsions.

Pharmaceutical formulations can be prepared by procedures known in theart. For example, the compounds can be formulated with commonexcipients, diluents, or carriers, and formed into tablets, capsules,suspensions, powders, and the like. Examples of excipients, diluents,and carriers that are suitable for such formulations include thefollowing: fillers and extenders such as starch, sugars, mannitol, andsilicic derivatives; binding agents such as carboxymethyl cellulose andother cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; moisturizing agents such as glycerol; disintegrating agentssuch as calcium carbonate and sodium bicarbonate; agents for retardingdissolution such as paraffin; resorption accelerators such as quaternaryammonium compounds; surface active agents such as cetyl alcohol,glycerol monostearate; adsorptive carriers such as kaolin and bentonire;and lubricants such as talc, calcium and magnesium stearate, and solidpolyethyl glycols.

The compounds can also be formulated as elixirs or solutions forconvenient oral administration or as solutions appropriate forparenteral administration, for instance by intramuscular, subcutaneousor intravenous routes. Additionally, the compounds are well suited toformulation as sustained release dosage forms and the like. Theformulations can be so constituted that they release the activeingredient only or preferably in a particular part of the intestinaltract, possibly over a period of time. The coatings, envelopes, andprotective matrices may be made, for example, from polymeric substancesor waxes.

The particular dosage of a compound of formula I required to inhibitacne or seborrhea in a non-topical administration, according to thisinvention will depend upon the severity of the condition, the route ofadministration, and related factors that will be decided by theattending physician. Generally, accepted and effective daily doses willbe from about 0.1 to about 1000 mg/day, and more typically from about 50to about 200 mg/day. Such dosages will be administered to a subject inneed of treatment from once to about three times each day, or more oftenas needed to effectively treat the symptoms.

For topical administration, the compounds may be formulated as is knownin the art for direct application to an area. Conventional forms forthis purpose include ointments, lotions, pastes, jellies, sprays, andaerosols. The percent by weight of a compound of the invention presentin a topical formulation will depend on various factors, but generallywill be from 0.5% to 95% of the total weight of the formulation, andtypically 1-25% by weight.

The compositions can take the form of an aqueous or anhydrous solutionor dispersion, or alternatively the form of an emulsion or suspension.

These compositions can contain pharmaceutically acceptable vehicles andadjuvants which are well known in the prior art. It is possible, forexample, to prepare solutions using one or more organic solvent(s) thatis/are acceptable from the physiological standpoint, chosen, in additionto water, from solvents such as acetone, ethanol, isopropyl alcohol,glycol ethers such as the products sold under the name "Dowanol",polyglycols and polyethylene glycols, C₁ -C₄ alkyl esters of short-chainacids, preferably ethyl or isopropyl lactate, fatty acid triglyceridessuch as the products marketed under the name "Miglyol", isopropylmyristate, animal, mineral and vegetable oils and polysiloxanes.

The compositions according to the invention can also contain thickeningagents such as cellulose and/or cellulose derivatives. They can alsocontain gums such as xanthan, guar or carob gum or gum arabic, oralternatively polyethylene glycols, bentones and montmorillonites, andthe like.

These compositions according to the invention can also contain, incombination, other active agents such as retinoic derivatives,antibacterial agents, antiinflammatories, and steroids such aspregnenolone. Examples of such agents include benzoyl peroxide,tetracyclins, erythromycin, minocycline, clindamycin, ampicillin,trimethoprim, sulfamethoxazole, vitamin A, and isotretinoin; forseborrhea; LHD in Nivea oil and glucorticoiods.

It is possible to add, if necessary, an adjuvant chosen fromantioxidants, surfactants, other preservatives, film-forming,keratolytic or comedolytic agents, perfumes and colourings.

For example, among antioxidants, t-butylhydroquinone, butylatedhydroxyanisole, butylated hydroxytoluene and α-tocophrol and itsderivatives may be mentioned.

The galenical forms chiefly conditioned for topical application take theform of creams, milks, gels, dispersions or microemulsions, lotionsthickened to a greater or lesser extent, impregnated pads, ointments orsticks, or alternatively the form of aerosol formulations in spray orfoam form or alternatively in the form of a cake of soap.

FORMULATIONS

In the formulations which follow, "Active ingredient" means a compoundof formula I.

Formulation 1: Gelatin Capsules

Hard gelatin capsules are prepared using the following:

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Active ingredient 0.1-1000                                                    Starch, NF        0-650                                                       Starch flowable powder                                                                          0-650                                                       Silicone fluid 350 centistokes                                                                  0-15                                                        ______________________________________                                    

The ingredients are blended, passed through a No. 45 mesh U.S. sieve,and filled into hard gelatin capsules.

Examples of specific capsule formulations of the compound of formula 1wherein R² is piperidino, (raloxifene), that have been made includethose shown below:

Formulation 2: Raloxifene capsule

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Raloxifene        1                                                           Starch, NF        112                                                         Starch flowable powder                                                                          225.3                                                       Silicone fluid 350 centistokes                                                                  1.7                                                         ______________________________________                                    

Formulation 3: Raloxifene capsule

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Raloxifene        5                                                           Starch, NF        108                                                         Starch flowable powder                                                                          225.3                                                       Silicone fluid 350 centistokes                                                                  1.7                                                         ______________________________________                                    

Formulation 4: Raloxifene capsule

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Raloxifene        10                                                          Starch, NF        103                                                         Starch flowable powder                                                                          225.3                                                       Silicone fluid 350 centistokes                                                                  1.7                                                         ______________________________________                                    

Formulation 5: Raloxifene capsule

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Raloxifene        50                                                          Starch, NF        150                                                         Starch flowable powder                                                                          397                                                         Silicone fluid 350 centistokes                                                                  3.0                                                         ______________________________________                                    

The specific formulations above may be changed in compliance with thereasonable variations provided.

A tablet formulation is prepared using the ingredients below:

Formulation 6: Tablets

    ______________________________________                                        Ingredient        Quantity (mg/tablet)                                        ______________________________________                                        Active ingredient 0.1-1000                                                    Cellulose, microcrystalline                                                                     0-650                                                       Silicon dioxide, fumed                                                                          0-650                                                       Stearate acid     0-15                                                        ______________________________________                                    

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 0.1-1000 mg of active ingredientare made up as follows:

Formulation 7: Tablets

    ______________________________________                                        Ingredient          Quantity (mg/tablet)                                      ______________________________________                                        Active ingredient   0.1-1000                                                  Starch              45                                                        Cellulose, microcrystalline                                                                       35                                                        Polyvinylpyrrolidone                                                                              4                                                         (as 10% solution in water)                                                    Sodium carboxymethyl cellulose                                                                    4.5                                                       Magnesium stearate  0.5                                                       Talc                1                                                         ______________________________________                                    

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 500°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.1-1000 mg of medicament per 5 mL dose aremade as follows:

Formulation 8: Suspensions

    ______________________________________                                        Ingredient           Quantity (mg/5 ml)                                       ______________________________________                                        Active ingredient    0.1-1000   mg                                            Sodium carboxymethyl cellulose                                                                     50         mg                                            Syrup                1.25       mg                                            Benzoic acid solution                                                                              0.10       mL                                            Flavor               q.v.                                                     Color                q.v.                                                     Purified water to    5          mL                                            ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor, and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

The following composition is prepared:

Formulation 9

    ______________________________________                                        Ingredient       Quantity (mg/5 ml)                                           ______________________________________                                        Hydroxypropylcellulose                                                                         1.5 g                                                        Active Ingredient                                                                              1.5-30 g                                                     Isopropanol qs   100 g                                                        ______________________________________                                    

Formulation 10

The following composition is prepared:

    ______________________________________                                        Ingredient       Quantity (mg/5 ml)                                           ______________________________________                                        Hydroxypropylcellulose                                                                         1.5 g                                                        Ethyl lactate    15.0 g                                                       Active Ingredient                                                                              1.5-30 g                                                     Isopropanol qs   100 g                                                        ______________________________________                                    

Formulation 11

The following composition is prepared:

    ______________________________________                                        Ingredient        Quantity (mg/5 ml)                                          ______________________________________                                        Hydroxypropylcellulose                                                                          1.0 g                                                       Butylated hydroxytoluene                                                                        0.02 g                                                      Active Ingredient 1.5-25 g                                                    Ethanol qs        100 g                                                       ______________________________________                                    

Formulation 12

The following composition is prepared:

    ______________________________________                                        Ingredient         Quantity (mg/5 ml)                                         ______________________________________                                        Hydroxypropylcellulose                                                                            1.5 g                                                     Butylated hydroxytoluene                                                                         0.01 g                                                     C.sub.8 -C.sub.12 fatty acid triglycerides                                                       10.0 g                                                     Active Ingredient  1.5-30 g                                                   Isopropanol qs      100 g                                                     ______________________________________                                    

Formulations 9-12 take the form gels, and are intended for the topicaltreatment of acne.

Formulation 13

The following composition is prepared:

    ______________________________________                                        Ingredient         Quantity (mg/5 ml)                                         ______________________________________                                        Isopropanol        46.0 g                                                     Active Ingredient  1.0-15 g                                                   C.sub.8 -C.sub.12 fatty acid triglycerides                                                       49.0 g                                                     ______________________________________                                    

Formulation 14

The following composition is prepared:

    ______________________________________                                        Ingredient         Quantity (mg/5 ml)                                         ______________________________________                                        Ethanol            69.0 g                                                     Ethyl lactate      10.0 g                                                     Active Ingredient  1.5-20 g                                                   C.sub.8 -C.sub.12 fatty acid triglycerides                                                       30.0 g                                                     ______________________________________                                    

Formulation 15

The following composition is prepared:

    ______________________________________                                        Ingredient         Quantity (mg/5 ml)                                         ______________________________________                                        Isopropanol        47.0 g                                                     Acetone            10.0 g                                                     Ethyl lactate      10.0 g                                                     Active Ingredient  1-15 g                                                     C.sub.8 -C.sub.12 fatty acid triglycerides                                                       30.0 g                                                     ______________________________________                                    

Formulation 16

The following composition is prepared:

    ______________________________________                                        Ingredient        Quantity (mg/5 ml)                                          ______________________________________                                        Ethanol           95.08 g                                                     Butylated hydroxytoluene                                                                         0.02 g                                                     Active Ingredient 1.5-25 g                                                    ______________________________________                                    

Formulations 13, 14, 15, and 16 take the form of a lotion.

Formulation 17

The following composition is prepared:

    ______________________________________                                        Ingredient       Quantity (mg/5 ml)                                           ______________________________________                                        White vaseline   50.0 g                                                       Liquid paraffin  15.0 g                                                       Refined paraffin wax                                                                           32.0 g                                                       Active ingredient                                                                              1-20 g                                                       ______________________________________                                    

Formulation 18

The following composition is prepared:

    ______________________________________                                        Ingredient       Quantity (mg/5 ml)                                           ______________________________________                                        White vaseline   50.0 g                                                       Liquid paraffin  13.0 g                                                       Refined paraffin wax                                                                           32.0 g                                                       Active Ingredient                                                                              1-20 g                                                       ______________________________________                                    

Formulations 17 and 18 takes the form of a stick.

ASSAYS

Assay 1

Each of from between two and twenty patients selected for the clinicalevaluation is placed in a comfortable environment, i.e., comfortabletemperature, humidity, lighting, etc. These patients have refrained fromstrenuous exercise and consumption of spicy foods for the twelve hoursprior to the evaluation. An area of the body which contains a largenumber of sebaceous glands affected by seborrhea or acne, such as theforehead, is wiped with a gauze pad to remove accumulated lipids. Apatch of the skin is taped off, forming a rectangle sized 2.5 by 1.8 cm.A pad of cigarette paper or other suitable absorbent material sized 2.5by 1.8 cm is placed on the test area of the skin. The absorbent materialmust have first been defatted with ether prior to the placement on thetest area to remove background lipids. The pad is the held in place witha bandage. After fifteen minutes the pad is replaced with a fresh pad(test pad). This procedure removes the background lipids in the skin sothe true rate of lipid production by the sebaceous glands may bedetermined. The test pad is left in place for three to six hours andthen removed. The test pad is then extracted with ether to emove thelipids and the ether evaporated. The residual lipids are then weighed.The result is expressed as the number of sebaceous lipids (mg) per 10cm² per hour. The patient then takes either 30-400 mg/day of the activeingredient by the oral route, or applies a topical formulationcontaining 5-20% by weight of the active ingredient daily, both forthree to nine weeks. The above described test pad methodology isrepeated several times throughout administration of the activeingredient to monitor progress. This assay may also be performed onanimals to verify utility. A positive effect is reflected by a decreaseof the rate of sebaceous gland lipid production.

Assay 2

Between two and twenty patients are enrolled in this clinical protocoland are initially evaluated by direct observation of the skin andlesions thereon. This is done by choosing one cm² sections of affectedskin and the number and type of lesion (comedos, seborrehic lesions,etc.) is noted. The areas normally used are the cheeks, scalp or back.The patient then takes either 30-400 mg/day of the active ingredient bythe oral route, or applies a topical formulation containing 5-20% byweight of the active ingredient daily, both for three to nine weeks Theareas of the skin being evaluated are checked during the period ofadministration. Care must be taken to evaluate the same areas and inorder to accomplish this a small mark or marks may be made on the skinby a permanent marker. A positive result is reflected by a reduction inthe number and/or severity of the lesions in the monitored areas of theskin.

Utility of the compounds described herein is exhibited by the positiveresults observed in one or both of the above assays.

We claim:
 1. A method of inhibiting acne or seborrhea comprisingadministering to a human in need of treatment an effective amount of acompound having the formula ##STR5## wherein R¹ and R³ are independentlyhydrogen, --CH₃, ##STR6## wherein Ar is optionally substituted phenyl;R² is selected from the group consisting of pyrrolidine,hexamthylenemino, and piperidino; or a pharmaceutically acceptable saltof solvate thereof.
 2. The method of claim 1 wherein said compound isthe hydrochloride salt thereof.
 3. The method of claim 1 wherein saidcompound is ##STR7## or its hydrochloride salt.
 4. A topical formulationcomprising a compound of claim 1 and one or more topical formulationadditives.
 5. The method of claim 4 where said formulation comprises atleast one other active agent.